Project Summary Molecular simulations have played important roles in biochemical and biophysical sciences. Advances have been made that have allowed extensive simulations of increasingly complex systems with growing time and size scales. The Amber force field consortium is a team of investigators with highly complementary expertise in areas ranging from QM calculations, polarizable and fixed charged force fields, and solvent models, to force field validation. This synergy has helped to unify and enable Amber force field development. The long-term goals of this consortium are to develop force fields that can reproduce biological structure, dynamics and interactions without sacrificing the computational efficiency necessary to reach biologically relevant timescales. With the release of Amber polarizable force field ff12pol, the consortium has made significant inroads towards accurately representing the energetic surfaces of proteins and nucleic acids. Furthering these advances, the Amber force field consortium proposes to develop parameters and simulation methodologies that are part of the foundation of molecular simulation platform to push the Amber force field efforts to the next level. A key focus of this consortium is to not only develop general, reliable and widely applicable force fields for proteins, nucleic acids and drug-like molecules, but to validate the force fields via thorough testing and comparison to other available methods and force fields. At present, the choices to make in terms of the model (polarization, charge model, solvent representation) are still active research questions. This proposal is broad-reaching in that multiple approaches will be investigated. A key objective of the consortium is to further enhance the close collaboration that allows ideas to be tested and investigated much more quickly. The proposed work is broadly categorized in the following areas. 1) Development of a polarizable general Amber force field model will allow more accurate representation of diverse sets of drug-like molecules interacting with biomolecules represented by the polarizable force fields; 2) Development of continuum solvent models with explicit consideration of atomic polarization will extend the range of applicability of polarizable force field and enable efficient and accurate free energy calculations; 3) The simulation methodology and the associated parameters will be rigorously scrutinized and critically assessed through direct comparisons with experiments on an extensive set of model systems.